Origin of the myotonic dystrophy type 1 mutation in Mexican population and influence of Amerindian ancestry on CTG repeat allelic distribution.

Myotonic dystrophy type 1 is caused by expansion of a CTG trinucleotide repeat situated in the DMPK gene. Worldwide genetic studies suggest a single or limited number of mutational events cause the disease. However, distribution of CTG alleles and disease incidence varies among ethnicities. Due to the great ethnic diversity of the Mexican population, the present study was aimed at analyzing the impact of different lineages in shaping the CTG-repeat allelic distribution in the contemporary Mexican-Mestizo population as well as to shed light on the DM1 ancestral origin. Distribution of CTG-repeat alleles was similar among Mestizo and Amerindian subpopulations with (CTG)11-13 being the most frequent alleles in both groups, which implies that Mexican-Mestizo allelic distribution has been modeled by Amerindian ancestry. We diagnosed a relatively high number of cases, consistent with the high frequency of large-normal alleles found in Mexican subpopulations. Haplotype analysis using various polymorphic-markers in proximity to DMPK gene indicates that a single founder mutation originates myotonic dystrophy type 1 in Mexico; however, Y-STR haplogroups data and the presence of pre-mutated and large normal alleles in Amerindians support the hypothesis that both European and Amerindian ancestral chromosomes might have introduced the disease to the Mexican population, which was further disseminated through mestizaje.

Interethnic variation of the MMP-9 microsatellite in Amerindian and Mexican Mestizo populations: considerations for genetic association studies.

We studied the interethnic variation of the MMP-9 microsatellite in the Mestizo and Amerindian populations using blood samples collected from 435 healthy unrelated individuals from the Central Valley of Mexico. DNA samples were genotyped using the -90 (CA)12-27 repeat near the MMP transcriptional start site using capillary electrophoresis. Our data were compared with those from African, Asian, and European populations (N = 729). Both Mestizo and Amerindian populations were in Hardy-Weinberg equilibrium (P ≥ 0.05). However, strong genetic heterogeneity was found within the Mestizo population (94%, P ≤ 0.0001), which exhibited the highest frequency of Amerindian, African, and European alleles. Likewise, Amerindians showed 6.7% variation among populations (P ≤ 0.0001), suggesting a genetic substructure potentially associated with linguistic affiliations. These findings were corroborated with principal component and population differentiation analyses, which showed relative proximity among the Mestizos and their historical parental populations: Asian (FST ≥ 0.05), European (FST ≥ 0.09), and African (FST ≥ 0.02). Nevertheless, important differences were found between Mestizo and Nahuas (P ≤ 0.0001), and between Mestizo and Me'Phaas (P ≤ 0.0001). These findings highlight the importance of determining local-specific patterns to establish the population variability of MMP-9 and other polymorphic markers. Validation of candidate markers is critical to identifying risk factors; however, this depends on knowledge of population genetic variation, which increases the possibility of finding true causative variants. We also show that dissimilar ethnic backgrounds might lead to spurious associations. Our study provides useful considerations for greater accuracy and robustness in future genetic association studies.